荷兰拉德布大学医学中心Alexander Hoischen团队发现重症COVID-19年轻男性中存在基因变异。2020年7月24日，《美国医学会杂志》发表了这一成果。

COVID-19可发生在年轻男性、无既往病史的患者中。一些人可能具有原发性免疫缺陷，易患由SARS-CoV-2引起的严重感染。

为了探讨年轻COVID-19患者中原发性免疫缺陷与存在基因变异是否有相关性，研究组招募因重症COVID-19而进入重症监护病房（ICU）的年轻（年龄<35岁）、无病史的成对兄弟。2020年3月23日至4月12日，荷兰4家医院的ICU收治了来自2个无关家庭的4名男子。快速临床全外显子组测序结果用于鉴定潜在的单基因病因。随后，在从患者和家属分离的原代免疫细胞中进行了基本的基因和免疫学测试，以鉴定任何免疫缺陷。

4例男性患者的平均年龄为26岁（21-32岁），无重大慢性病史。他们在因严重COVID-19而出现呼吸功能不全，需要在ICU中进行机械通气之前，身体状况一直良好。通气支持的平均时间为10天，ICU的平均住院时间为13天。有1名患者死亡。对患者进行快速临床全外显子组测序，并在可用的家族成员中进行分离，确定了TLR7 X染色体功能缺失变体。

在家族1的成员中，鉴定出了母亲遗传的4-核苷酸缺失；被感染的家族2成员携带了一个错义变体。在患者的原发性外周血单个核细胞中，通过TLR7激动剂咪喹莫特刺激后IRF7、IFNB1和ISG15的mRNA表达显著降低来测量，下游I型干扰素（IFN）信号转录下调。为响应咪喹莫特的刺激，患者的II型IFN-γ产生亦减少。

总之，在4例严重COVID-19的年轻男性患者中，鉴定出了与I型和II型IFN反应受损相关罕见的功能丧失的X染色体TLR7变体。这些初步发现有助于了解COVID-19的发病机理。

附：英文原文

Title: Presence of Genetic Variants Among Young Men With Severe COVID-19

Author: Caspar I. van der Made, Annet Simons, Janneke Schuurs-Hoeijmakers, Guus van den Heuvel, Tuomo Mantere, Simone Kersten, Rosanne C. van Deuren, Marloes Steehouwer, Simon V. van Reijmersdal, Martin Jaeger, Tom Hofste, Galuh Astuti, Jordi Corominas Galbany, Vyne van der Schoot, Hans van der Hoeven, Wanda Hagmolen of ten Have, Eva Klijn, Catrien van den Meer, Jeroen Fiddelaers, Quirijn de Mast, Chantal P. Bleeker-Rovers, Leo A. B. Joosten, Helger G. Yntema, Christian Gilissen, Marcel Nelen, Jos W. M. van der Meer, Han G. Brunner, Mihai G. Netea, Frank L. van de Veerdonk, Alexander Hoischen

Issue&Volume: 2020-07-24

Abstract: Importance  Severe coronavirus disease 2019 (COVID-19) can occur in younger, predominantly male, patients without preexisting medical conditions. Some individuals may have primary immunodeficiencies that predispose to severe infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Objective  To explore the presence of genetic variants associated with primary immunodeficiencies among young patients with COVID-19.

Design, Setting, and Participants  Case series of pairs of brothers without medical history meeting the selection criteria of young (age T; p.[Val795Phe]). In primary peripheral blood mononuclear cells from the patients, downstream type I interferon (IFN) signaling was transcriptionally downregulated, as measured by significantly decreased mRNA expression of IRF7, IFNB1, and ISG15 on stimulation with the TLR7 agonist imiquimod as compared with family members and controls. The production of IFN-γ, a type II IFN, was decreased in patients in response to stimulation with imiquimod.

Conclusions and Relevance  In this case series of 4 young male patients with severe COVID-19, rare putative loss-of-function variants of X-chromosomal TLR7 were identified that were associated with impaired type I and II IFN responses. These preliminary findings provide insights into the pathogenesis of COVID-19.

DOI: 10.1001/jama.2020.13719

Source: https://jamanetwork.com/journals/jama/fullarticle/2768926